Throughout this application various publications are referred to by number in parentheses. Full citations for these references may be found at the end of the specification. The disclosures of these publications and of all books, patents and patent application publications cited herein, are hereby incorporated by reference in their entirety into the subject application to more fully describe the art to which the subject invention pertains.
Pancreatic ductal adenocarcinoma, synonymous to pancreatic cancer, is the 4th leading cause of cancer deaths. The “silent killer” is characterized by its metastatic behavior (3) before the primary tumor can be detected, resulting in a five-year survival rate of only 4%. Current cancer treatments, i.e. surgery, followed by radiation and/or chemotherapy, are ineffective against metastases. Gemcitabine and erlotinib, FDA-approved drugs for pancreatic cancer treatment, improve median survival by approximately six months in advanced stage patients (1-3), emphasizing the need for new alternative therapies for pancreatic cancer. One such approach could be Listeria monocytogenes-based cancer therapy.
This laboratory discovered that a highly attenuated Listeria (Listeriaat) provides a therapeutic approach that is particularly useful against metastatic cancer. Myeloid derived suppressor cells (MDSC) are normally a major problem in cancer vaccination because they strongly suppress T cell and natural killer (NK) cell responses and promote angiogenesis (4-10), resulting in the development of metastases. However, when infected with Listeriaat MDSC protect Listeriaat from immune clearance through their immune suppressive character (Chandra et al., unpublished results), and deliver Listeriaat safely to the tumor microenvironment where it infects and kills tumor cells through high levels of reactive oxygen species (ROS) (11). Also, Listeriaat-specific cytotoxic T lymphocytes (CTL) kills tumor cells, because infected tumor cells present Listeriaat antigens (11). Importantly, in normal tissues that lack immune suppression Listeriaat is rapidly cleared by macrophages, NK cells and CTL (11,12) which makes such treatment safe for human use.
Targeted radionuclide therapy has proven to be successful in treatment of several types of cancer and employs radiolabeled small molecules, monoclonal antibodies, peptides and other tumor-targeting vehicles (13). The radioactive particles emitted by the radionuclides physically destroy the cancerous cells and such therapies are not subject to multidrug resistance mechanisms. There have been attempts to utilize targeted radionuclide therapy in the form of radiolabeled tumor specific antibodies (Ab) (radioimmunotherapy) for treatment of pancreatic cancer. However, radioimmunotherapy of pancreatic cancer has shown very modest results both pre-clinically (14-16) and in cancer patients with unresectable liver metastases (17). New choices of targeting vehicles are needed to make targeted radionuclide therapy successful in treatment of pancreatic cancer.
The present invention addresses the need for new targeted cancer therapies by providing “radiobacteria”, including radiolisteria, to treat tumors, including inoperable tumors.